Regulatory T cells are known to play roles in the maintenance of self-tolerance and immunological homeostasis by suppressing immune responses both pathologically and physiologically (NPL 1).
For example, the cells which were initially CD4+CD25− are activated by stimulation with various factors to become CD4+CD25+ regulatory T cells, and eventually account for about 5 to 10% of peripheral CD4+ T cells. The CD4+CD25+ regulatory T cells start to express FoxP3 protein along with the differentiation of the CD4+ T cells (NPL 2, 3). Intercellular interactions as well as humoral factors such as TGF-beta (herein also referred to as TGF-b) and IL-10 have been shown to play important roles in this process (NPL 4).
The FoxP3 protein is considered to serve as a specific marker for the activation of regulatory T cells because its expression can be observed not only in CD4+CD25+ T cells but also in CD8+CD25+ T cells (NPL 5). Further, FoxP3 protein plays an important role in manifestation of functions of the regulatory T cell, because a naive T cell in which FoxP3 is forced to be expressed starts to show a phenotype like a regulatory T cell (NPL 6). Thus, FoxP3 gene is believed to be a master gene to regulate the differentiation and function of regulatory T cells (NPL 1).
The regulatory T cells are known to suppress immune responses (NPL 1) by exceptionally suppressing function of other cells (NPL 7). Its mechanism is yet to be known, but it has been suggested that the suppression of other cells functions is dependent on the intercellular interaction and that CTLA-4 is involved in the suppression (NPL 8). In particular, CTLA-4 was shown to be also involved in the differentiation of regulatory T cells (NPL 8).
While a host immunity is present in the body of a cancer patient to attack and eliminate the cancer, the cancer cells have a system to evade the defense by the host immunity. For example, it has been shown both in vitro and in vivo that the immune responses against cancer cells were changed when regulatory T cells were deleted in the presence of the cancer cells (NPL 17). Since increases in the number of regulatory T cells have been observed in stomach cancer (NPL 9, 10), rectal cancer (NPL 11), pancreatic cancer (NPL 12, 13), lung cancer (NPL 14) and glioma (NPL 17), they are considered to be involved in a system of the cancer cells to evade the immunity. However, its mechanism is yet to be known, and the way how the cytokines derived from the regulatory T cells affect the system is still a matter of controversy (NPL 17).
Since a deficiency in regulatory T cells causes severe autoimmune diseases (NPL 15), a mechanism common to the autoimmunity and the cancer immunity is considered to be present (NPL 16). The regulatory T cells are known to be involved in the suppression of immunological reactions to the cancer cells as well as the hyperimmune responses such as autoimmunity and allergic reactions through the suppression of immune responses (NPL 1).